Hydrogenation process



Patented Aug. 3, 1954 HYDROGENATION PROCESS Joseph Levy, Union, andGeorge Albert Bernotsky, Newark, N. J., assignors to Nopco ChemicalCompany, Harrison, N. J., a corporation of New Jersey No Drawing.Application September 29, 1949, Serial No. 118,711

20 Claims.

This invention relates to ahydrogenation process and more particularlyto a process for the hydrogenation of piperidone compounds tohydroxyp-iperidine compounds.

There are various processes disclosed in' the prior art for producinghydroxypiperidine compounds from piperidones. Such processes are ofparticular value in. the production of the compound arecoline which isan alkaloid that is utilized by veterinarians as an anthelmintic.

In German Patent No. 485,139, the compoundN-methyI-3-carbomethoxy-4-piperidone is reducedto the corresponding4-hydroxypi-peridine compound by hydrogenation in the presence of aplatinum oxide catalyst. This hydrogenation reaction requires a periodof approximately 50 hours to accomplish. Also, it requires relativelylarge amounts of the very expensive platinum oxide catalyst. In anarticle in J. Gen. Chem. (U. S.S. R.) 11, 934-8 (1941), (C'. A. 37,381), Dankova et a1. disclosed the hydrogenation ofN-methyl-3-carbethoxy-i-piperidone with sodium amalgam. The Dankovaprocedure is rather impractical and quite cumbersome inasmuch as atleast 20 parts ofsodium amalgam are required for each part of piperidonewhich is to be hydrogenated. Furthermore, sodium amalgam is a difiicultsubstance to prepare on a large scale and necessitates the handling oflarge amounts of the expensive and toxic mercury.

Dankova mentions that thereduction may be carried out using. eitherplatinum oxide or Haney nickel as a catalyst. Apparently, however,Dankova considered the sodium amalgam procedure to be the mostsatisfactory since that procedure was the one he gave in the. detaileddescription of his process. As pointed out above, the use of platinumoxide as a catalyst is an expensive procedure and requires very longreaction times to complete the hydrogenation. Apparently the use ofRaney nickel by Dankova was not,satisfactory or he would have used thatin his preferred procedure rather than employing the toxic, expensiveand cumbersome sodium amalgam. Ugryumov in Compt. Rend. Acad. Sci, U. S.S. R. 2-3, 48-52 (1940), (C. A. 35, 3644) describes the hydrogenation ofN-methyl-3-carbomethoxy-4-piperidone employing a catalyst prepared froman alloy containing 17% nickel and 83% aluminum. was prepared bycrushing the alloy to the size of a pea, then treating it for 3 hourswith a 2% solution of caustic soda, and thereafter washing it with waterto a neutral reaction. The hydrogenation process of Ugryumov isnot setforth in The catalyst of Ugryumov 2 detail as far as results and yieldswhich were obtained are concerned. In this process, the hydrogenation iscarried. out on the piperidone ester as the free base in 80% alcohol-20%water solution. Thus a disadvantage of this procedure is that itrequires the isolation of the relatively unstable piperidone. ester freebase. This compound is rather difiicult to isolate without losses,particularly on a large scale, since it has been shown to readilyundergo an irreversible change to a solid material thus reducing theyield of the desired keto ester, e. g. see Cook and Reed, J. C. S.

399 (1945) and Craig and Tarbell, J. A. C. S. 71, 465 (1949).

In copending application Serial No. 724,243, now Patent No. 2,506,458 ofLawrence H. Knox, filed January 24, 1947, a very highly improved processfor producing arecol-ine is disclosed and claimed. In that process thehydrogenation of the piperidone compound to a hydroxypiperid-ine wascarried out far more satisfactorily than by any of the means disclosedin the prior art. It was foundthat if a small percentage of either thefree piperidone or fre piperidine was present in a solution of thehydrochloride salt of the piperidone; the piperidone could behydrogenated to the hydroxypiperidine inthe presence of a platinum oxidecatalyst in a very short time and in the presence of a far smalleramount of platinum oxidev than was required in the proc ess of theGerman patent referred to above. The hydrogenation process of patentapplication Serial No. 724,243 although-it is a great advance over theprior art processes for the hydrogenation ofN-methyl-3-carbalkoXy-l-piperidones is still a rather expensiveprocedure inasmuch as it necessitates the use of the very expensiveplatinum oxide catalyst. In fact the cost of the catalyst makes up alarge percentage of the total production cost when the hydrogenation iscarried out by that process.

It would be highly desirable if one could employ the very inexpensiveHaney nickel catalyst in the hydrogenation of theN-methyl-3-carbalkoxy-4-piperidones to the hydroxypiperidines. McElvainand coworkers in three recent articles, J. A. C. S. 68, 1049 (1946); J.A. C. S. 70, 1826 (1948); and J. A. G. S. 71, 903 (1949), described thereduction of various piperidone compounds with Raney nickel catalysts.Intwo of the procedures of McElvain et 'al., the compounds which werebeing hydrogenated did not have ester groups thereon while in the otherprocess, the compound whichwas being hydrogenated was N -benzoyl 3carbethoxy 4 piperidone. This compound, of course, is quite similar tothe N- methyl-3-carbalkoxyl piperidones since it has an ester group onthe 3 position. In these procedures McElvain and coworkers found itnecessary to employ very high pressures, e. g. 2200 lbs/sq. in., andrelatively high temperatures, e. g. '75-125 C. Naturally such reactionconditions require relatively elaborate and expensive equipment,particularly for plant operations, in order to carry out the reactions.

It is the object of the present invention to provide an improvedprocedure for the hydrogenation of N-alkyl-3-carbalkoxy-i-piperidones.

Another object of the invention is to provide a procedure for thehydrogenation of N-methyl- 3-carbalkoxy-e-piperidones which is moreeconomical than previous hydrogenation processes.

A further object of the invention is to provide an improved procedurefor the hydrogenation of N-methyl-3-carbalkoxy-1-piperidones wherein thehydrogenation can be carried out at a relatively low pressure andtemperature.

Other objects of the invention will in part be obvious and will in partappear hereinafter.

We have discovered that the above and other objects of the invention maybe accomplished by dissolving an N-alkyl-3carbalkoxyl-piperidone as thefree base in any aromatic or saturated aliphatic hydrocarbon solventsuch as benzene, toluene, xylene, cumene, hexane, heptane, octane,nonane, decane, methyl cyclohexane and similar solvents and thenhydrogenating the piperidone in the hydrocarbon solvent in the presenceof a relatively large amount of Fancy nickel catalyst. It has been foundthat the free piperidone ester is relatively quite stable in suchsolvents and very high yields of the desired piperidine compounds areobtained by such a hydrogenation process. Furthermore, the hydrogenation may be readily carried out at room temperature and at arelatively low pressure, e. g. from about 2 to about 5 atmospheres.

Raney nickel catalyst is a well known hydrogenation catalyst anddescriptions of this catalyst may be found in U. S. Patent No. 1,628,190of Fancy, in J. A. C. S. 54, 4116 (1932) and in the textbook OrganicSyntheses, Volume 21, page 15, published in 1941 by John Wiley and Sons,Inc., New York. In general, this catalyst is prepared from an alloy madeup of about 50% of aluminum and about 50% of nickel. The finely powderedalloy is treated with a 20% solution of sodium or potassium hydroxideuntil the alkali dissolves the aluminum in the alloy leaving the nickelin a finely divided and highly active form. The nickel is then washedseveral times with water and thereafter stored under water or some othersolvent until it is to be used. As is well known, this catalyst is quitecheap as compared to platinum oxide catalysts.

In the process of our invention, any ester of an N-alkyll-piperidonecompound having a carboxyl group substituted in the ring may behydrogenated to the corresponding hydroxypiperidine ester. Preferably weemploy our process to convert N-methyl-3-carbalkoxy-4-piperidones to thecorresponding N methyl 3 carbalkoxyi-hw droxypiperidines and moreparticularly we employ our process for converting N-methyl3-carbomethoxyi-piperidone carbethoxy-d-piperidone to the correspondinghydroxypiperidine compounds.

As pointed out above, any aromatic or saturated aliphatic hydrocarbonsolvent may be employed in the process of our invention although andN-methyl-3- we prefer that such solvents should be solvents having aboiling point of between about 50 C. and about 180 C. The amount of thehydrocarbon solvent which is employed is not critical although, ofcourse, it should be sufficient to dissolve completely the piperidoneester which is to be hydrogenated.

In carrying out the process of the invention, the solutions of thepiperidones in the hydro carbon solvents are preferably obtained withoutisolating the relatively unstable piperidone bases. In most cases inprocesses for the production of arecolinc, Nmethyl-3-carbomethoxy-4-piperidone will be available as the sodium orother alkali metal enolate salt prepared from the condensation ofbis-(B-carbomethoxyethyl)- methylamine with an alkali metal condensingagent, such as sodium or potassium or a hydride or methylate thereof.This alkali metal enolate salt may be dissolved in water and the freebase liberated by first adding a slight excess over an equivalent amountof an acid such as acetic acid, hydrochloric acid, etc., to the solutionfollowed by adding an excess of a weak alkali such as sodium orpotassium carbonate. Thereafter the free base may be extracted from theaqueous medium with a suitable solvent although preferably the solventwhich is to be employed in the hydrogenation procedure is utilized asthe extracting solvent. The most convenient procedure and the one whichwe preferably employ in our process to liberate the free base from thesodium or other alkali metal enolate salt of the piperi done ester is todissolve the sodium or other alkali metal salt of the piperidone esterin water containing an excess of either sodium or potassium bicarbonatepreferably keeping the temperature of the mixture at or below about 20C. so as to minimize any likelihood of a small percentage of the estergroups being saponified during the reaction. The bicarbonate will reactwith the salt of the piperidone to convert the salt to the free basewith the sodium or other alkali metal combining with the bicarbonate toproduce a carbonate compound. Thereafter the free base may be readilyextracted from the aqueous solution with a solvent such as one of thoseto be used in the hydrogenation procedure. A very convenient manner inwhich to accomplish this is to slowly add the alkali metal salt of thecondensation product to an aqueous solution of either sodium ofpotassium bicarbonate containing sufficient bicarbonate to convert allof the piperidone salt to the free base which solution is overlaid withthe desired amount of solvent to be used in extracting out the freebase. The alkali metal salt is added to this mixture as the mixture israpidly stirred. Thus the salt reacts almost immediately with thebicarbonate in the aqueous solution and immediately subsequent theretothe free base is extracted from the aqueous solution by the hydrocarbonsolvent. In this manner the solvent solution of the relativelyunstablepiperidone ester is obtained without the necessity of isolatingthe free base. On completion of the extraction of the free piperidoneester from the aqueous solution, the solvent solution thereof which isobtained is dried in some suitable manner such as over anhydrous sodiumsulfate. To insure complete recovery of the free piperidone, the aqueoussolution may be further extracted with a few small portions of thehydrocarbon solvent, which extracts are then combined with the originalsolvent solution.

- utilized.

' in our process.

'droxypiperidine ester.

tion with some inert salt such as sodium chloride 'orisodium-sulfate orsome other inert salt. However, this is not necessary and the free basemay be recovered from the aqueous solution merely by extracting theaqueous solution with the desired water-immiscible solvent.

The hydrocarbon solvent solution of the free base is then admixed'withthe desired amount of Raney nickel catalyst. A relatively large quantityof Raney nickel catalyst is employed in the process of our invention ascompared to the amount of Raney nickel catalyst employed in the usualhydrogenation procedures. Preferably, we

employ about 1 part of Raney nickel catalyst for each 2 parts of thefree base which is to be hydrogenated and in all cases at least about 1part of the catalyst for each 4 parts of free base is employed. Ifdesired, an amount of catalyst equal to the weight of the free base maybe used. In carrying out the hydrogenation in accordance with ourprocess, only relatively low hydrogen pressures are required as comparedto the prior art hydrogenation procedures.

Thus hydrogen pressures of from about 2 to about 5 atmospheres, i. e.from about to about 75 lbs/sq. in., are suflicient to accomplish thedesired hydrogenation although, if desired, moderately' elevatedpressures may be employed of course, e. g. about 250 to 300 lbs/sq. in.Furthermore, the hydrogenation can be readily accomplished at roomtemperature as compared to the relatively high temperatures required inprevious processes where Raney nickel catalyst was Of course, ifdesired, temperatures higher than room temperature can be employed Thetime required for the hydrogenation reaction to be accomplished by ourprocess is no longer than the time required in many of the prior artprocesses and is much shorter than the time required in some of theprior art processes. In most cases the desired hydrogenation will beaccomplished in .from about 6 to 8 hours. Ifdesired, one may carry outthe well known ferric chloride test on the reaction products todetermine whether any piperidone ester was not converted to the hy- Inthis test, a violet coloration is obtained when a small amount of ferricchloride is added to a solution if a compound which exhibits keto-enoltautomerism,

such as one of the piperidone esters, 'is present in the solution.

On completion of the hydrogenation reaction,

"the hydroxypiperidine compound is readily isolated from thehydrogenation reaction mixture by filtering the mixture to remove thecatalyst therefrom and then distilling the hydrocarbon solvent,preferably at a reduced pressure. The residue will be the desiredhydroxypiperidine ester in a relatively pure form. The pure ester maythen be obtained by distilling this crude tion is much-more economicalthan any of the "prior art procedures. Furthermore, the process of ourinvention gives very high yieldsxoithe'desired. hydroxypiperidinecompound. Although our process is employed principally for thehydrogenation of N-methyl-3-carbomethoxy-14-piperidone to thecorresponding hydroxypiperidine compound which hydroxypiperidinecompound is subsequently convertedby dehydration to arecoline, it isalso highly suitable for the hydrogenation ofN-methyl-3-carbethoxyi-piperidone to the corresponding hy roxypiperidinewhich on dehydration gives homo-arecoline.

For a fuller understanding of the nature and objects ofthe invention,reference maybe .had to the following examples which are given merely asfurther illustrations of the invention andare not to be construed in alimitingsense:

Example I The dry sodium enolate of N-methyl-3-carbomethoxy-4-piperidone obtained by the cyclization of 0.2 mole ofbis-(,B-carbomethoxyethyl)-methylamine with sodium was added withvigorous stirring to a mixture of 20 gms. of sodium sulfate, 30 gms. ofsodium bicarbonate and 75 cc. of water overlaid with cc. of toluene.After the enolate was completely dissolved in the mixture, the toluenelayer was separated from the aqueous layer. Then the aqueous layer wasextracted three times with 35 cc. portions of toluene. The originaltoluene layer and the toluene extracts were then combined and dried oversodium sulfate, filtered and then treated with hydrogen at about 4atmospheres pressure in the presence of about 15 gms. of Raney nickelcatalyst. Reduction of the N- methyl-3-carbomethoxy-4-piperidone in thetoluene proceeded rapidly and after absorption of hydrogen ceased, thecatalyst was filtered from the solution and the solvent then removed invacuo on a steam bath from the hydroxypiperipoint of l23-125 C. at 12mm.

Example II Another hydrogenation was carried out in essentially the samemanner as in Example I except that the amount of catalyst employed wasonly about 17% of the weight of the free piperidone base. It was foundthat reduction did not take place with this amount of catalyst andtherefore an additional amount of catalyst sumcient to bring the totalquantity of catalyst up to about 25% of the weight of the freepiperidone base was added. Reduction of the piperidone then proceededsatisfactorily although at an appreciably slower rate than in Example Iwhere the quantityof catalyst was equal to about 50% of the weight ofthe free piperidone. It is evident, therefore, that it is necessary toemploy at least about 1 part of catalyst for each 4 parts of the freepiperidone and preferably we employ about 1 part of catalyst for each 2parts of the'free piperidone.

Example 111 solvent. The naphtha which was employed'had a boiling pointof between about 115 and C.

Amixture made up of 75 cc. of water containing gms. of sodiumbicarbonate was overlaid with 150 cc. of the naphtha. No sodium sulfatewas employed as in Example I to aid in salting out the free piperidone.Two-tenths mole of the dry sodium enolate of N-methyl-3-carbomethoxy-4-piperidone was added to this reaction mixture with stirring, keeping thetemperature at or be low room temperature. As soon as all of the soroomtemperature and at a hydrogen pressure of about 4 atmospheres.

On completion of the hydrogenation, the catalyst was filtered from thesolution and the naphtha then evaporated therefrom in vacuo on a steambath. The crude product which was obtained was purified by distilling itin vacuo. The pure hydroxypiperidine was obtained in a yield equal to76% of the theoretical yield.

Example IV In this example the reduction of the piperidone was carriedout in xylene. The dry sodium enolate ofN-methyl-3-carbomethoxy-4-piperidone obtained by the cyclization of 0.1mole of -bis-(B-carbomethoxyethyl) methylamine was .added with vigorousstirring to a mixture of 30 cc. of water and 15 gms. of sodiumbicarbonate which was overlaid with 100 cc. of xylene, keeping thetemperature at or below room temperature. When all of the sodium salthad dissolved in the mixture, the xylene layer was separated therefromand the aqueous layer was extracted three times with 50 cc. portions ofxylene. The combined xylene extracts, including the original xylenelayer, were dried over anhydrous sodium sulfate, filtered and then about7.5 gms. of Raney nickel catalyst were added thereto. The xylenesolution was then subjected to hydrogenation at .room temperature undera hydrogen pressure of about 50 lbs/sq. in. gauge pressure. Reductionproceeded quite rapidly with the greater part of the reduction (85%-90%)taking place in about two hours. In order to insure complete reduction,however, the hydrogenation was allowed to proceed for a few hourslonger. The catalyst was then filtered from the solution and the xyleneremoved from the solution by evaporation in 'vacuo on a steam bath. Thecrude hydroxypi- "peridine was purified by distillation under reducedpressure. A yield of 83.2% of the desired hydroxypiperidine wasobtained.

Example V A hydrogenation identical with that of Example IV with theexception that the xylene was replaced with heptane was carried out. Itwas found, however, that the hydrogenation did not proceed quite asrapidly in the heptane as in the xylene so after about four hours anadditional gms. of catalyst was added to the heptane solution. Thereduction then proceeded fairly rapidly, giving a yield of the desiredhydroxypiperidine of 81%.

Having described our invention what we claim I as new-and desire tosecure by Letters Patent is:

1. A process for hydrogenating an N-alkyl-3- carbalkoxy--piperidone toan N-alkyl-S-car balkoxy-4-hydroxypiperidine which comprises dissolvingan N-alkyl-3-carbalkoxy-4-piperidone in a solvent selected from thegroup consisting of aromatic hydrocarbons and saturated aliphatichydrocarbons, and hydrogenating the piperidone in the solvent solutionin the presence of at least about one part of Raney nickel catalyst foreach four parts of the piperidone, said hydrogenation being effected atabout room temperature and under a hydrogen pressure of from about 2 toabout 20 atmospheres.

2. A process for hydrogenating N-methyl-3- carbomethoxy-i-piperidone toN-methyl-B-carbomethoxy-4-hydroxypiperidine which comprises dissolvingthe piperidone in a solvent selected from the group consisting ofaromatic hydrocarbons and saturated aliphatic hydrocarbons, andhydrogenating the piperidone in the solvent solution in the presence ofat least about one part of Raney nickel catalyst for each four parts ofthe piperidone, said hydrogenation being effected at about roomtemperature and under a hydrogen pressure of from about 2 to about 20atmospheres.

3. A process for hydrogenating Nmethyl-3 carbethoxyi-piperidone toN-methyl 3 carbethoxy-4-hydroxypiperidine which comprises dissolving thepiperidone in a solvent selected from the group consisting of aromatichydrocarbons and saturated aliphatic hydrocarbons, and hydrogenating thepiperidone in the solvent solution in the presence of at least about onepart of Raney nickel catalyst for each four parts of the piperidone,said hydrogenation being effected at about room temperature and under ahydrogen pressure of from about 2 to about 20 atmospheres.

4. The process of claim 2 wherein the hydrocarbon solvent is benzene.

5. The process of claim 2 wherein the hydrocarbon solvent is toluene.

6. The process of claim 2 wherein the hydrocarbon solvent is xylene.

7. A process for converting N-methyl-3-carbomethoxy-d-piperidone toN-methyl-3-carbomethoxy-e-hydroxypiperidine which comprises admixing analkali metal enolate salt of the piperidone with a mixture of an aqueoussolution of at least a stoichiometrically equivalent weight of an alkalimetal bicarbonate and a solvent selected from the group consisting ofaromatic hydrocarbons and saturated aliphatic hydrocarbons, completelydissolving the alkali metal enolate salt of the piperidone in themixture thus liberating the free piperidone from the salt, sop-- aratingthe hydrocarbon solvent and the free piperidone which has becomedissolved therein from the mixture, ,and then hydrogenating thepiperidone in the hydrocarbon solvent in the presence of at least aboutone part of Raney nickel catalyst for each four parts of the piperidone,said hydrogenation being effected at about room temperature and under ahydrogen pressure of from about 2 to about 20 atmospheres.

8. The process of claim 7 wherein the hydrocarbon solvent is benzene.

9. The process of claim 7 wherein the hydrocarbon solvent is toluene.

10. The process of claim '7 wherein the hydrocarbon solvent is xylene.

11. A process for converting N-Inethyl-3-carbomethoxyl-piperidone toN-methyl-3-carbomethoxyi-hydroxypiperidine which comprises adding analkali metal enolate salt of the piperidone to an aqueous solution of analkali metal bicarbonate containing an amount of bicarbonate at leaststoichiometrically equivalent to the amount of piperidone salt, mixingthe piperidone salt with the aqueous solution until the salt iscompletely dissolved at which time the free piperidone will have beenliberated from the salt, extracting the free piperidone from the aqueousmixture with a solvent selected from the group consisting of aromatichydrocarbons and saturated aliphatic hydrocarbons, and hydrogenating thepiperidone in the hydrocarbon solvent in the presence of at least aboutone part of Baney nickel catalyst for each four parts of the piperidone,said hydrogenation being effected at about room temperature and under ahydrogen pressure of from about 2 to about 20 atmospheres.

12. The process of claim 11 wherein the hydrocarbon solvent is benzene.

13. The process of claim 11 wherein the hydrocarbon solvent is toluene.

14. The process of claim 11 wherein the hydrocarbon solvent is xylene.

15. The process of claim 2 wherein the hydrogenation is carried out atabout room temperature and under a hydrogen pressure of about two toabout five atmospheres.

16. The process of claim 7 wherein the hydrogenation is carried out atabout room temperature and under a hydrogen pressure of about two toabout five atmospheres.

17. The process of claim 11 wherein the hydrogenation is carried out atabout room temperature and under a hydrogen pressure of about two toabout five atmospheres.

18. The process of claim 2 wherein the hydrogenation is carried out inthe presence of at 19 least about one part of Raney nickel catalyst foreach two parts of piperidone.

19. The process of claim '7 wherein the hydrogenation is carried out inthe presence of at least about one part of Fancy nickel catalyst foreach two parts of piperidone.

20. The process of claim 11 wherein the hydrogenation is carried out inthe presence of at least about one part of Raney nickel catalyst foreach two parts of piperidone.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 1,695,666 Schirmacher et a1. Dec. 18, 1928 1,980,638 Scheuinget a1. Nov. 13, 1934 2,018,680 Lazier Oct. 29, 1935 2,477,842 WennerAug. 2, 1949 FOREIGN PATENTS Number Country Date 485,139 Germany Oct.31, 1929 520,201 Great Britain Apr. 17, 1940 OTHER REFERENCES

1. A PROCESS FOR HYDROGENATING AN N-ALKYL-3CARBALKOXY-4-PIPERIDONE TO ANN-ALKYL-3-CARBALKOXY-4-HYDROXYPIPERIDINE WHICH COMPRISES DISSOLVING ANN-ALKYL-3-CARBALKOXY-4-PIPERIDONE IN A SOLVENT SELECTED FROM THE GROUPCONSISTING OF AROMATIC HYDROCARBONS AND SATURATED ALIPHATICHYDROCARBONS, AND HYDROGENATING THE PIPERIDONE IN THE SOLVENT SOLUTIONIN THE PRESENCE OF AT LEAST ABOUT ONE PART OF RANEY NICKEL CATALYST FOREACH FOUR PARTS OF THE PIPERIDONE, SAID HYDROGENATION BEING EFFECTED ATABOUT ROOM TEMPERATURE AND UNDER A HYDROGEN PRESSURE OF FROM ABOUT 2 TOABOUT 20 ATMOSPHERES.